Diisopropylethylamine → (1-[2-(5-{6-[4-(2-{1-[2-methoxycarbonylamino-2-(tetrahydropyran-4-ylidene)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester

HRID 72034노트

반응식

HRID 72034 반응식
[CH3:1][O:2][C:3]([NH:5][C:6](=[C:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([OH:9])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.Cl.[CH3:43][O:44][C:45](=[O:89])[NH:46][CH:47]([C:51]([N:53]1[CH2:57][CH2:56][CH2:55][CH:54]1[C:58]1[NH:59][C:60]([C:63]2[CH:72]=[CH:71][C:70]3[C:65](=[CH:66][CH:67]=[C:68]([C:73]4[CH:78]=[CH:77][C:76]([C:79]5[NH:80][C:81]([CH:84]6[CH2:88][CH2:87][CH2:86][NH:85]6)=[N:82][CH:83]=5)=[CH:75][CH:74]=4)[CH:69]=3)[CH:64]=2)=[CH:61][N:62]=1)=[O:52])[CH:48]([CH3:50])[CH3:49].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:43][O:44][C:45](=[O:89])[NH:46][CH:47]([C:51]([N:53]1[CH2:57][CH2:56][CH2:55][CH:54]1[C:58]1[NH:59][C:60]([C:63]2[CH:72]=[CH:71][C:70]3[C:65](=[CH:66][CH:67]=[C:68]([C:73]4[CH:78]=[CH:77][C:76]([C:79]5[NH:80][C:81]([CH:84]6[CH2:88][CH2:87][CH2:86][N:85]6[C:7](=[O:9])[C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])=[C:10]6[CH2:15][CH2:14][O:13][CH2:12][CH2:11]6)=[N:82][CH:83]=5)=[CH:75][CH:74]=4)[CH:69]=3)[CH:64]=2)=[CH:61][N:62]=1)=[O:52])[CH:48]([CH3:50])[CH3:49]

참가 물질

7

반응물 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59611013Methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acidHCID 66620476{2-methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester trihydrochloride

생성물 1

HCID 66620834(1-[2-(5-{6-[4-(2-{1-[2-methoxycarbonylamino-2-(tetrahydropyran-4-ylidene)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester수율 50%

시약·촉매·용매 2

HCID 6228Dimethylformamide용매2회HCID 8857Ethyl Acetate용매

실험 절차

To a solution of methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid methyl ester (141 mg, 0.62 mmol) in methanol (1.8 mL) was added an aqueous LiOH solution (1M, 1.8 mL, 1.8 mmol). The resulting solution was stirred at room temperature for 16 hours and then washed with ethyl acetate. The ethyl acetate washing was discarded and the aqueous layer was acidified with concentrated HCl. The acidified aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with brine, dried (MgSO4), and concentrated to give methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid. To a solution of methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid (23 mg, 0.11 mmol) in dimethylformamide (0.6 mL) was added HATU (41 mg, 0.11 mmol). After stirring for 5 minutes, a solution of {2-methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester trihydrochloride (50 mg, 0.068 mmol) in dimethylformamide (0.6 mL) was added to the reaction, followed immediately by diisopropylethylamine (85 μL, 0.49 mmol). The reaction was stirred for 1 hour at room temperature then diluted with ethyl acetate. The organic layer was washed successively with saturated aqueous NaHCO3 solution, water and brine, dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H) to yield {1-[2-(5-{6-[4-(2-{1-[2-methoxycarbonylamino-2-(tetrahydropyran-4-ylidene)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (28 mg, 50%). LCMS-ESI+: calculated for C46H52N8O7: 828.95; observed [M+1]+: 830.32. 1H-NMR: 400 MHz, (CD3OD) δ: 8.24-8.07 (m, 3H), 7.96-7.76 (m, 7H), 7.45-7.34 (m, 2H), 5.28-5.18 (m, 2H), 4.27-4.23 (m, 1H), 4.05-3.98 (m, 1H), 3.94-3.86 (m, 1H), 3.84-3.41 (m, 12H), 2.48-1.98 (m, 13H), 1.02-0.90 (m, 6H) ppm.

후처리

  1. stirringThe reaction was stirred for 1 hour at room temperature
  2. washThe organic layer was washed successively with saturated aqueous NaHCO3 solution, water and brine
  3. dry with materialdried (MgSO4)
  4. concentrationconcentrated
  5. custompurified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H)

출처 및 근거

ORD 기록
ord-0a709b812adb4f7e911e71ecf2faa04a
출처 데이터셋
uspto-grants-2014_09
특허 번호
US08822430B2

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